Diseases Studied

Introduction

The Folding@home project (FAH) is dedicated to understanding protein folding, the diseases that result from protein misfolding and aggregation, and novel computational ways to develop new drugs in general. Here, we briefly describe our goals, what we are doing, and some highlights so far.

A distributed computing project must not only run calculations on millions of PCs, but such projects must produce results, especially in the form of peer-reviewed publications, public lectures, and other ways that disseminate the results from FAH to the greater scientific community. Below, we detail our progress in these areas.

Note that most updates are announced in the main Folding@home blog, but we will periodically update this page. For the latest news, please see the blog.

What is protein folding and how is it related to disease?

Proteins are necklaces of amino acids, long chain molecules.

Proteins are the basis of how biology gets things done. As enzymes, they are the driving force behind all of the biochemical reactions that make biology work. As structural elements, they are the main constituent of our bones, muscles, hair, skin and blood vessels. As antibodies, they recognize invading elements and allow the immune system to get rid of the unwanted invaders. For these reasons, scientists have sequenced the human genome — the blueprint for all of the proteins in biology — but how can we understand what these proteins do and how they work?

However, only knowing this sequence tells us little about what the protein does and how it does it. In order to carry out their function (e.g. as enzymes or antibodies), they must take on a particular shape, also known as a “fold.” Thus, proteins are truly amazing machines: before they do their work, they assemble themselves! This self-assembly is called “folding.”

What happens if proteins don’t fold correctly?

Diseases such as Alzheimer’s disease, Huntington’s disease, cystic fibrosis, BSE (Mad Cow disease), an inherited form of emphysema, and even many cancers are believed to result from protein misfolding. When proteins misfold, they can clump together (“aggregate”). These clumps can often gather in the brain, where they are believed to cause the symptoms of Mad Cow or Alzheimer’s disease.

Which diseases or biomedical problems are you currently studying?

Alzheimer’s Disease (AD)

AD is caused by the aggregation of relatively small (42 amino acid) proteins, called Abeta peptides. These proteins form aggregates which even in small clumps appear to be toxic to neurons and cause neuronal cell death involved in Alzheimer’s Disease and the horrible neurodegenerative consequences. It’s a challenge to study these aggregates, even with simulations.

We have many calculations being performed on AD. Our primary goals are the prediction of AD aggregate structure for rational drug design approaches as well as further insight into how AD aggregates form kinetically (hopefully paving the way for a method to stop the AD aggregate formation). We have made great progress towards this end.

2005

We submitted our first paper on FAH results.

FAH researchers Vishal Vaidyanathan and Nick Kelley presented the recent FAH results on AD at BCATS 2005. Their work won the best talk award in 2005.

Prof. Vijay Pande presented recent FAH work on AD at the National Parkinson’s Foundation conference (in the session on AD and its connections to PD).

2006 We have submitted our first paper for peer review and we’re working on the next 2 paper right now. We’re very excited about the results!

The first of the papers has come out (see paper #58 on our Results page: “Simulating oligomerization at experimental concentrations and long timescales: A Markov state model approach”). In many ways, this paper is the “tip of the iceberg” for the Folding@home activities in AD, with a lot more interesting results to come, especially in terms of experimental tests of our predictions and interesting new possibilities for new drugs and AD therapeutics. So, while we’re excited that this result is now past peer review, we’re even more excited for what’s coming down the pipeline, waiting peer review.

We presented our results regarding new possible drugs (small molecule leads) to fight Alzheimer’s Disease at a recent meeting at Stanford, supported by the NIH Roadmap Nanomedicine center and NIH grants. We may have multiple small molecules which appear to inhibit toxicity of Abeta, the protein which is the toxic element in Alzheimer’s Disease. Considering all the technology development that had to be done in the first five years, these results have come very quickly (in the last 3 years), which is exciting. We are now looking to apply these methods to other protein misfolding diseases (we have pilot projects for Huntington’s Disease underway).

2009 We have had some exciting results regarding new possible drug leads for Alzheimer’s. We hope to be submitting these soon for publication.

2010 We have been working closely with the Nanomedicine Center for Protein Folding on pushing our lead compounds forward. They have gone from the test tube to the first round of testing beyond that (onto tissue) and we’re continuing to refine the compounds based on the results obtained so far. Also, FAH researcher Dr. Yu-Shan Lin has been awarded a BioX Postdoctoral Fellowship for her proposed work on Alzheimer’s Disease simulation.

2012 We’re very excited to report on our progress towards our goal to develop new small molecule drug candidates for AD. In a paper just published in the Journal of Medicinal Chemistry, we report on tests of predictions from earlier Folding@home simulations, and how these predictions have led to a new strategy to fight Alzheimer’s Disease. These results have been a long time in coming and in many ways represents a major achievement for Folding@home (FAH) in general. While this is not a cure, it is a major step towards our final goal, some light at the end of the tunnel. The next steps, now underway in our lab, are to take this lead compound and help push it towards a viable drug. We’re very excited that the directions set out in this paper do appear to be bearing fruit in terms of a viable drug (not just a drug candidate). We hope to have more results in the coming months!

2013 We are continuing our work with AD in terms of repurposing an existing drug against the leads we have found from Folding@home. The benefit of this approach is that this drug could hit the market considerably quicker and also (if the repurposed drug is a generic) at a considerably lower cost.

Huntington’s Disease (HD)

HD is caused by the aggregation of a different type of proteins. Some proteins have a repeat of a single amino acid (glutamine, often abbreviated as “Q”). These poly-Q repeats, if long enough, form aggregates which cause HD. We are studying the structure of poly-Q aggregates as well as predicting the pathway by which they form. Similar to AD, these HD studies, if successful, would be useful for rational drug design approaches as well as further insight into how HD aggregates form kinetically (hopefully paving the way for a method to stop the HD aggregate formation).

2006 We are currently in the process of submitting our first paper on FAH results.

2007 Nick Kelley has been working on a new collaboration with Judith Frydman’s group to computationally test a new hypothesis for HD aggregation found in the Frydman lab.

2008

Prof. Pande has presented the results on HD at a variety of Stanford internal conferences and meetings. People have been excited and interested in the results.

We have also started to apply the drug design methods used in Alzheimer’s to HD.

2009 Our new paper #62: “The predicted structure of the headpiece of the Huntington protein and its implications for Huntington’s Disease.” just came out in the Journal of Molecular Biology.

2010 FAH researcher Dr. Veena Thomas has proposed a novel therapeutic strategy for HD and this proposal looks to be funded by NIH (as of September 22, 2010 still pending). This strategy is particularly exciting since it could be a quick way to bring the results from computation directly to a therapeutic.

2013 FAH researcher Dr. Diwakar Shukla has continued work on HD. He has new results on the behavior of the HTT protein and will be presenting his results at the Annual AiChE meeting in San Francisco.

Cancer and P53

Half of all known cancers involve some mutation in p53, the so-called guardian of the cell. P53 is a tumor suppressor which signals for cell death if their DNA gets damaged. If these cells didn’t die, their damaged DNA would lead to the strange and unusual growths found in cancer tumors and this growth would continue unchecked, until death. When p53 breaks down and does not fold correctly (or even perhaps if it doesn’t fold quickly enough), then DNA damage goes unchecked and one can get cancer. We have been studying specific domains of p53 in order to predict mutations relevant in cancer and to study known cancer related mutants.

2005

Our first work on cancer has recently been published.

We are expanding FAH’s p53 work to other related p53 systems

We are getting some interesting results from recent new FAH p53 projects.

Two new sets of projects have completed and two new papers are being readied for peer-reviewed publication.

2006 FAH researcher Dr. Lillian Chong presented her work on p53 at a lecture at several US Universities.

2007 Plans have started to take a new approach for using FAH to fight cancer: to develop novel chaperonin inhibitors. FAH researcher Del Lucent is taking the lead. See this blog post for more information on Del’s research.

2008 Del has presented his plans to the NIH Nanomedicine center with a very positive response. Planning for the lab side of this work has begun.

2009

Del has been involved in the development of new software methods (Ocker) for the chaperonin inhibitor project.

We’ve been using our new Protomol (Core B4) core to study the activation of src Kinase, an enzyme that is involved in the onset of some kinds of cancer.

2010 In collaboration with the Nanomedicine Center for Protein Folding, we have been using our methods to further push a chaperonin inhibitor. This next round will use new scoring functions from Andrej Sali’s lab at UCSF to push further what we could do in this area.

2012

Please see this blog post for Dr. John Chodera’s anti-cancer strategy involving kinases.

Dr. Peter Kasson has been applying his work on viruses to cancer, as many cancers are virus-associated.

At FAHcon 2012, Dr. Xuhui Huang presented our recent results of the molecular mechanisms of gene transcription. Transcription is the first step in reading genomic DNA, and regulation of this process plays a key role in cell differentiation and other fundamental processes. Misregulation of transcription is a major factor in cancer and other human diseases. Our simulation results are able to provide dynamic information for the transcription, and this dynamic information is largely inaccessible to present experimental techniques.

We’re studying the folding of ubiquitin, a small regulatory protein found in almost all cells in human body. It is part of a large regulatory system that labels other unneeded proteins for destruction. The ubiquitin system has an important role in regulating cellular growth and proliferation. As expected, alterations in the ubiquitin system could lead to uncontrolled accumulation of malignant proteins in cells and lead to cancer.

We are simulating many forms of Pin1 WW domain, a protein implicated in some cancers and Alzheimer’s disease. Understanding the role of mutations on misfolding can have important biomedical consequences.

We assisted Chris Garcia’s lab with their work with Interleukin 2 (IL-2), a protein which assists the immune system in fighting pathogens and cancer tumors. While injecting a patient with more IL-2 has been an effective cancer treatment, naturally occuring IL-2 has very serious side effects. We helped the Garcia lab to discover a form of IR-2 that was more “floppy”, which greatly increased its cancer-fighting potency. This means that it’s possible to admister theurapedic doses of it without causing the side effects. Stanford has applied for a patent, and several major pharmaceutical companies approached the Garcia lab about this discovery. Please see this paper and this article for more information.

2013 FAH researchers Dr. Diwakar Shukla and Dr. Morgan Lawrenz have been using Folding@home to understand the fundamental behavior of kinases, key molecular targets in cancer. A paper on these results and their impact on drug design for cancer has been submitted for peer review.

2014 The paper on the results of a kinase study conducted by Dr. Diwakar Shukla and his fellow researchers has been published. This kinase under investigation is c-src, which has been a major research interest of FAH since 2009. C-src is involved in the onset of numerous most feared human cancers, and is a key molecular target for therapeutic interventions. We discovered a unique drug-binding site on c-src, and binding drugs to it deters c-src’s full activation. We also captured c-src’s dynamic behaviors in unprecedented fine details via FAH simulations. This study has profound implications for increasing specificity of future anti-cancer drugs, thus could potentially reduce side effects associated with chemotherapy drastically. Please see this paper and these blog posts from March 23rd and 24th for more information.

Chagas Disease

In 2010, we have started a pilot project on Chagas Disease, a major disease in Latin America.2010 FAH/Pande Group researcher Paul Novick has applied ligand-based methods to Chagas disease and in collaboration with the SPARK project (UCSF) and the McKerrow Lab (UCSF) has started to test the results. The early results are looking promising, but it is very early to tell.

Malaria

2010 FAH/Pande Group researcher Dr. Veena Thomas has been building off methods used by PG member Paul Novick for Chagas to Malaria. This is very early stages, but with promising results from our Chagas disease work, this is a reasonable extension of that approach and of course could have a major impact on millions of people in the developing world.

Osteogenesis Imperfecta (OI)

In collaboration with other groups at Stanford (especially Dr. Teri Klein’s group at Stanford University Medical Center), we are looking at Collagen folding and misfolding. Collagen is the most common protein in the body and mutations in collagen leads to a very nasty disease called Osteogenesis Imperfecta (or OI for short). In many cases, OI is lethal and leads to miscarriage. However, 1 in 10,000 people have some sort of mutational in collagen. For many, where the mutation is not very serious, it lies unknown and misdiagnosed and leads to brittle bones and other more subtle problems. In others, however, mutations lead to more serious morphological disorders (as shown on the right).

We are starting to model collagen folding and misfolding in the 1000 series projects. Follow the link for more information.

2005 FAH’s first work on collagen has been accepted for publication

2006 FAH researcher Dr. Sangyhun Park presents his work on collagen at a lecture at Duke University

2007 Our paper on collagen folding has been accepted for publication.

2008 Our paper on collagen folding has come out.

For now, our Osteogenesis imperfecta stands still as a pilot project, with the bulk of our efforts going into AD and HD.

Diabetes

Prof. Xuhui Huang’s lab at the Hong Kong University of Science and Technology is studying the folding free energy landscape of the human islet amyloid polypeptide (hIAPP). hIAPP (also called amylin) is a peptide 37 amino acids in length, and its aggregation reduces working ß-cells in patients with Type 2 diabetes. Around 95% of patients with Type II diabetes exhibit large deposits of misfolded hIAPP (beta-sheet structure). Experiments show that hIAPP aggregation can induce cell death in insulin-producing beta cells, an effect that may be relevant to the development of type 2 diabetes. We aim to understand the process of hIAPP aggregation in order to design drugs to prevent it. We would like to thank all the Folding@home donors for your help to make our research possible.

Antibiotics

A key aspect of Folding@home research has been using computational methods to design new drugs, especially for Alzheimer’s Disease. At the University of Virginia, the Shirts lab is developing methods to leverage the power of Folding@home to develop new drugs to fight disease. Generally, small molecules work as drugs by binding very specifically to certain locations on important proteins. For example, an antibiotic works by binding to a protein on a bacteria, thus interfering with the pathogen’s internal workings seriously enough to disable or kill it. By targeting only protein sites that are unique to the pathogen, drugs can act extremely specifically, rather than harming the human body or desired microbes. The exact same principles can toggle very specific parts of our own body’s protein machinery on or off, allowing development of drugs that fight diseases of caused by breakdown, mutation, or malfunction our own cellular machinery, like Alzheimer’s Disease, heart disease, diabetes, and many other conditions.

However, it is very hard to calculate exactly how tightly a given small molecule will bind to a target protein, or even exactly where and by what mechanism it will bind. A number of computational methods are used in industry today to estimate the binding affinity of small molecules in the process of drug design, but they mostly rely on approximations that are computationally cheap and very approximate, rather than more expensive methods that have the potential to be much more accurate. With Folding@home, we now have the capability to perform rigorous evaluations of these more complete methods, understand their limits, and make them more efficient and reliable.

We’ve also been studying the ribosome, an amazing molecular machine that plays a critical role in biology, as it is the machine that synthesizes proteins. Because of this critical role, and some small but fundamental differences in the ribosomes of mammals and bacteria, the ribosome is the target for about half of all known antibiotics. These antibiotics typically work by preventing bacterial ribosomes from making new proteins, thus killing them. We have several projects on going to study the ribosome. Since the ribosome is so huge, these WUs are big WUs and have required us to push the state of the art of FAH calculations. However, with these new bigWUs, FAH is set up to study more and more complex problems, and if successful, with greater and greater biomedical impact.

2005

We are working on our first paper resulting from FAH’s ribosome simulations.

Prof. Pande presents ribosome results at a lecture at University of California at San Francisco (UCSF) Medical School, and later at Rice University.

2006

Prof. Pande presents ribosome result at the NIH Roadmap center on Nanomedicine.

We have submitted our first paper on the ribosome.

Our first work units for antibiotic drug design calculations are now running on Folding@home.

2007

We have received a grant from Stanford University to design and study novel antibiotics. This is a joint grant with the labs of Chaitan Khosla at Stanford’s Chemistry Department (who does small molecule synthesis, design, and some characterization) and Jody Puglisi at the Stanford Medical School (who studies the ribosome and antibiotics experimentally)

Relly Brandman is studying the ribosome tunnel as a target for novel antibiotics. There are already several antibiotics which target the ribosome tunnel (you may have already taken some, such as Erythromycin). She is studying how bacteria become resistant to these drugs, and her work centers around predicting novel antibiotics. If successful, we should be able to find novel types of antibiotics, which should hopefully be very useful in dealing with the major problem of drug resistance.

2008 Our first ribosome paper has come out in PNAS. See paper #59. Side-chain recognition and gating in the ribosome exit tunnel.

2009 Our second paper on the ribosome has been submitted for publication.

2011 We launched three A4 projects simulating the glycopeptide antibiotic vancomycin as well as the peptide chain it binds. Vancomycin is an important antibiotic of last resort, used to treat infections resistant to methicillin. Recently, cases of bacteria immune to vancomycin have been identified. The goal of these simulations is to study this resistance mechanism.

2012

We have been testing our methods with well-understood systems, and will soon be moving on try to design small molecules to treat AIDS (the HIV reverse transcriptase enzyme, required for DNA to replicate) and influenza (various proteins involved in virus cell entry). Such molecules will still require significant effort to make into drugs, since drugs also have to dissolve easily, penetrate cells, and not be broken down to quickly, but being able to predict more easily which molecules interact tightly with the intended targets will be a huge step in the right direction.

Dr. Gregory Bowman published an paper in the Proceedings of the National Academy of Sciences demonstrating a method that can disable proteins while they fold, rather than blocking them afterwards. This significantly increased our abilities to manipulate proteins for therapeutic purposes. He applied his techniques to proteins involved in immune dificiencies, HIV, and antibiotic resistance. Further research will require a lot more of your WUs, but we hope this type of approach can eventually lead to new pharmaceuticals. See this blog post for more information.

Parkinson’s Disease (PD)

We have also performed preliminary studies on a key protein implicated in Parkinson’s disease. Alpha-synuclein is a natively unfolded protein and its folding/misfolding (see figure on the right for misfolded aggregates) appears to be critically linked to PD. We are evaluating the application of various FAH methods to this problem.

2005

We have only done a pilot study on PD and are looking for funding to continue our work in this area.

Prof. Vijay Pande presented recent FAH work on AD at the National Parkinson’s Foundation conference (in the session on AD and its connections to PD).

For now, PD stands still as a pilot project, with the bulk of our efforts going into AD and HD.

Viral diseases

Viruses such as influenza and HIV pose major threats to human health and can be exceptionally difficult to treat. Most treatments concentrate on preventing viral replication, but another strategy is to keep the virus out in the first place.

In order to infect human cells, viruses must pass through the cell membrane. They have established special machinery to accomplish this process, which usually requires an activation signal, a protein conformational change, and then protein-membrane interactions to achieve cell entry. Prof. Kasson’s group studies this process to better understand and prevent viral diseases. We have focused on influenza both because it has a repeated history of causing widespread global disease (such as in 1918) and its victims are typically children under 2 and adults over 60. A similar virus today might easily kill in the range of 60 million people, and we’d like to be prepared. Influenza is an important model system for understanding other viruses such as HIV and cancer-causing viruses such as HPV, Heptatitis C virus, and Epstein-Barr virus. It may come as a surprise, but many cancers are virus-associated, and these form an important area for prevention. Based on advances Dr. Kasson made while at Stanford in collaboration with Dr. Pande, we have made good initial progress in understanding the basic reactions influenza employs to enter cells. We are now well positioned to start studying the details of how the virus works. More information is available here.

2007Dr. Peter Kasson’s lab is studying lipid vesicle fusion, a process relevant for many biological processes as well as relevant for disease and infection. Lipid vesicles are large assemblies of detergent-like molecules that are used to house and/or contain many different types of molecules in biology. Many viruses (“envelope viruses”) are housed in lipid vesicles, but so are the neurotransmitters in our brains. In order for these containers to be shuttled around (eg as neurotransmitters transmit thoughts in the brain or when viruses try to enter cells) lipid vesicles fuse with other vesicles or with cells (which are like giant lipid vesicles since cell walls are made of lipids). This process involves folding and other conformational changes.

2008 We published our work on some of the molecular interactions that occur during the initial stages of viral infection, and how they can impact current antivirus drugs.

2009

In the Journal of the American Chemical Society, we introduced a new method that can be used to test the pandemic risk of a virus. Swine influenza (pig flu) was more infectious among humans than bird flu due to the similarities of the cellular receptors between the human and swine upper respiratory tract.

Gregory Bowman is studying RNase H, a key component of HIV. By understanding the role of dynamics in its mechanism, we hope to be better able to design drugs to deactivate this enzyme.

2012

Dr. Kasson is looking at hemagglutinin, a viral protein that controls cell entry. Please see this blog post for more information.

We have done a lot of work on how influenza gets into cells to replicate in the first place. This is an important therapeutic target, and it’s also critical for understanding why viruses like H5N1 “bird flu” have not become efficiently transmissible between people. Some of our new work looks at the protein folding in the membrane required for viral entry. We have some exciting new results that we’ll blog about as soon as they’re published.

The Kasson group has recently published an article in Biochemistry on how influenza binds to cell-surface receptors and how computational techniques can be used for further analysis of this process.

2013 Pande group researchers have been recently looking into using our computational approaches for Dengue Fever as well, and have discovered a potential lead compound.

How are these advances possible?

In order to make breakthroughs using distributed computing, new methods are critical. Distributed computing is an unusual way to perform large-scale calculations. While it gives computer resources much greater than a typical supercomputer (e.g. the almost 200,000 actively processing CPUs in FAH vs. 5,000 in a typical supercomputer), these processors are connected by the Internet, not the high speed, low latency interconnects found in supercomputers. Thus, we must develop new methods to use FAH’s unusual computational paradigm and capabilities. Moreover, these methods must be tested.

Much of our work in the first years of FAH has been to develop and test these methods on model systems: small proteins that can be easily studied experimentally. With these experimental comparisons, we can test and validate our methods, as well as find out their limitations (which is critical for improving our methods). We are now focusing on theuraputic approaches to diseases.

To date, FAH has been very successful, with over 100 published works (as of September 2012) directly stemming from FAH calculations. We will continue to work on all fronts: new scientific cores, new server side algorithms, new models for proteins, and new questions related to testing our methods and applications to disease and other biomedical questions. Thanks to your help and algorithmic improvements on our end, our capabilities have drastically improved over the last twelve years.